The invention has for its object new stable activated derivatives of carbamic acid, particularly new stable activated carbamates, their process of preparation and their use for the preparation of urea.
The synthesis and applications of substituted ureas has for several years undergone great development. These compounds are present in a certain number of active principles now under development in the pharmaceutical industry as protease inhibitors of VIH, antagonists of the CCK-B receptor, or antagonists of endothelin1. Moreover, the oligoureas have been introduced as “scaffolds” for the creation of β-sheets2 or as mimics of the peptide skeleton3. The methods of formation of substituted ureas rely on the reaction of amines with carbonylation agents4, with isocyanates5 or with carbamates6.
In the field of research looking toward the development of new compounds with immunomodulatory activity, there is needed a simple method, not requiring the use of phosgene or of one of its derivatives, to produce easily peptidic analogs containing ureas or urea oligomers. In 1995, the Burgess group described for the first time the synthesis in solid phase of oligoureas. This was based on the use of isocyanate synthons derived from N-protected mono-phthalimide diamines. This strategy requires the preparation of protected mono-phthalimide diamines precursors and uses triphosgene as the carbonylation agent to obtain the corresponding isocyanate3a,3b. In a similar approach, the Schultz group used azido 4-nitrophenyl carbamates as pre-activated synthons3c,3d. More recently, 4-nitrophenyl carbamates obtained by the reaction of Boc-protected N-substituted ethylenediamines with 4-nitrophenyl chloroformate have been described as synthons for the synthesis of urea-peptoids by the Liskamp group3e. In short, there does not exist at present an easy synthesis route for activated monomers obtained from amino acids protected or not by an Fmoc, Boc or Z group, avoiding the use of phosgene (or its derivatives) and permitting the synthesis of urea oligomers as well as the easy incorporation of urea patterns in peptides. The activated carbamates are generally prepared by the reaction of amines with carbonates4c or chloroformates3e,6b, or by reaction of isocyanates with alcohols6a.